JPS624401B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing a polymer electrolyte complex (hereinafter referred to as PEC) useful as a medicine or medical material. PEC is obtained by reacting a positively charged polymer dissociable substituent with a negatively charged polymer dissociative substituent in an aqueous solution. This PEC has ion-selective permeability, semi-permeability, electrical conductivity, etc. due to various combinations of equivalence ratios, molecular weights, dissociative substituents, etc. of anion/positive polymer dissociative substituents, and ion exchange It is used as a material for membranes, membranes, ultra-diameter membranes, electrically conductive coding, etc. In particular, those made from dextran derivatives in aqueous solutions have excellent anticoagulant properties and biocompatibility, and are used in medicine and medical treatment. It is considered to be a promising material for artificial storage (for example, artificial storage devices). However, in general, PEC is poorly soluble in solvents, making it difficult to form composites with other materials, which limits its industrial use.Also, since it has anticoagulant properties, it can be used to impregnate hemostatic agents and hemostatic gauze that require procoagulant properties. It could not be used as a material for agents, etc. In view of the above, this invention is a polymer electrolyte composite that can be easily molded into composites with other materials, expands industrial applications, and can be used even in cases where procoagulability is required, compared to conventional PEC. The purpose of this research is to provide a method for producing PEC. The gist of this invention is to create a polyelectrolyte complex (PEC) in which a specific anionic partially substituted dextran and a specific cationic partially substituted polysaccharide or gelatin are reacted under acidic conditions at pH 3 or below. It is in the manufacturing method. This invention will be explained in detail below. The present inventors have found that when a specific anionic partially substituted dextran and a specific cationic partially substituted polysaccharide or gelatin are reacted under acidic conditions below PH3, the reaction occurs under approximately neutral conditions. The present invention was completed based on the discovery that there are differences in solubility in solvents and coagulability compared to the case in which the present invention is carried out.
The reason for the difference in solubility in solvents and coagulability is as follows. Under acidic conditions, the anionic group of the anionic partially substituted product is inhibited from dissociating. Therefore, the polymer electrolyte complex obtained by reacting an anionic partially substituted product with a cationic partially substituted polysaccharide or gelatin (cationic) under acidic conditions of pH 3 or less is In addition to ionic bonds, it contains many hydrogen bonds between anionic groups and CH ₂ OH or OH groups. On the other hand, most of the polymer electrolyte complexes obtained by a similar reaction under neutral conditions are ionic bonds. Here, the anionic partially substituted product of dextran refers to a product in which a part of the hydroxyl group of dextran is dissociated in an aqueous solution and replaced with a negatively charged dissociative group. The degree of substitution used in this invention is
It is 0.3-3 mol/AGU of dextran sulfate or carboxylmethyl dextran. In addition, a cationic partially substituted polysaccharide refers to a polysaccharide in which a portion of the hydroxyl groups dissociates in an aqueous solution and becomes positively charged. The natural product used in this invention is chitosan, and the semi-synthetic product is diethylaminoethyldextran with a degree of substitution of 0.1 to 3 mol/AGU. Gelatin is a derived protein obtained by hydrolyzing collagen, and its main components are glycine and proline, which dissociate in an aqueous solution and become positively charged. As the acid used in this invention, hydrochloric acid, acetic acid, etc. are preferable. Next, an aqueous solution of the above anionic partially substituted dextran (including a water-soluble salt) or a 0.05 to 5% aqueous solution adjusted to PH3 or less with the above acid, and a cationic partially substituted polysaccharide ( (contains water-soluble salts) or gelatin adjusted to PH3 or less with the above acid.
A white precipitate is obtained by stirring and mixing 0.05-5% aqueous solution in various equivalent ratios, preferably at 20-60°C for about 30-60 minutes. This white precipitate is separated from the reaction solution by centrifugation or filtration, washed thoroughly with water, dehydrated with methanol, and dried in vacuum to obtain the desired PEC. The PEC obtained by the method of this invention is usually in the form of white powder or granules, but if necessary, the PEC powder may be fed into a mold of a molding machine and vacuum compressed at a pressure of about 10 t/cm ² to form tablets. It is possible. Since the PEC obtained by the method of the present invention has the above-mentioned structure, as shown in the examples below, it is more insoluble and less soluble than the conventional PEC obtained by reacting under almost neutral conditions. It becomes soluble in solvents, making it easy to form composites with other materials, expanding its industrial applications.It also has remarkable procoagulant properties, making it particularly useful for hemostatic agents and hemostatic gauze impregnation agents. It is effective as a material for medicines and medical devices that require accelerating properties. In addition, obtained by the method of this invention
Like conventional PEC, PEC has excellent ion permselectivity, semipermeability, electrical conductivity, biocompatibility, etc., and can be used as ion exchange membranes, membranes, ultra membranes, and electrically conductive coatings. It goes without saying that it can be used as medicine, medicine, and medical equipment. Examples of the present invention using various combinations of anionic partially substituted dextran and cationic partially substituted polysaccharide or gelatin and their test data are shown below. Note that DS is an abbreviation for sodium dextran sulfate, and the intrinsic viscosity is the value in a 2M NaCl solution at 37°C. The procoagulant test method is as described above.
Form PEC into a tablet, add 0.1ml of ACD blood, add 0.01ml of 0.1M calcium chloride, place on a watch glass, allow a coagulation reaction in a 37°C water bath for 8 minutes, and then measure the amount of thrombus formed. do. The amount of thrombus generated on the glass surface under the same conditions is taken as 100%. When this thrombus amount value is less than 100%, the anticoagulant property is 100%.
When larger, it has procoagulant properties. Example 1 DS (S content = 18.8%, intrinsic viscosity = 0.274dl/
g) Commercially available chitosan prepared with 125 c.c. of 0.1% aqueous solution and hydrochloric acid to pH 0.26 (hydrochloric acid concentration 1%) (N content = 7.8
%, produced by Tokyo Kasei Co., Ltd.) and stirred and mixed at room temperature for about 30 minutes to obtain a white precipitate, which was separated and purified in the same manner as above to obtain a white powder of PEC.
Obtained 219 mg. This PEC had an N content of 3.6%, an S content of 10.37%, and an N/S molar ratio of 0.79. Example 2 DS prepared with PH2.6 (acetic acid concentration 2%) with acetic acid
(S content = 18.2%, intrinsic viscosity = 0.0276dl/g)4
% aqueous solution 44c.c. and acetic acid to pH2.6 (acetic acid concentration 2%)
Commercially available special grade gelatin (N content = 17.6%,
Manufactured by Merck Co., Ltd., isoelectric point = 6.5) 1% aqueous solution
80c.c. under the same conditions as Example 1 and purified by PEC.
0.55 g of white powder was obtained. This PEC has N content = 14
%, S content = 3.4%, and N/S molar ratio = 9.3. Example 3 DS adjusted to PH0.1 (hydrochloric acid concentration 1.5%) with hydrochloric acid
(S content = 18.4%, intrinsic viscosity = 0.27dl/g) 0.1%
PH0.1 with aqueous solution 480c.c. and hydrochloric acid (hydrochloric acid concentration 1.5%)
Diethylaminoethyldextran hydrochloride (N content = 5.0%, Mw = 1 million) 0.1% aqueous solution prepared in
160c.c. under the same conditions as Example 1 and purified by PEC.
0.196 g of white powder was obtained. This PEC had an N content of 3.5%, an S content of 9.1%, and an N/S molar ratio of 0.88. Example 4 Carboxymethyl dextran (degree of substitution 0.7 mol/AG) prepared with hydrochloric acid to pH 0. (hydrochloric acid concentration 4%)
U, Mw = 1 million) 0.3% aqueous solution 240 c.c. and PH with hydrochloric acid
Diethylaminoethyldextran hydrochloride (N content = 4.8%, Mw =
2 million) 0.2% aqueous solution was reacted and purified under the same conditions as in Example 1 to obtain 130 mg of white powder of PEC. this
PEC has N content = 2.0% CH ₃ COO ^- content = 10%,
The N/CH ₃ ^COO molar ratio was 0.85. Comparative Example 1 The same DS and chitosan as in Example 1 were PHed with hydrochloric acid.
The aqueous solution prepared in 6.5 was purified by reaction in the same amount and under the same conditions to obtain 200 mg of white powder of PEC. this
PEC is N content = 3.85%, S content = 10%, N/S
The molar ratio was 0.88. Here, the infrared absorption spectra of the PEC (A) obtained in Example 1, the PEC (B) obtained in Comparative Example 1, and the mixture of DS and chitosan were taken as shown in FIG. The solid line indicates PEC (A), the dotted line indicates PEC (B), and the dashed line indicates a mixture of DS and chitosan (hereinafter referred to as mixture). Absorption that was not observed in the mixture was observed in PEC (A) and PEC (B) near 1510 cm ^-1 . This is thought to be due to a bond between the NH ₃ ⁺ group of chitosan and the SO ₃ ^- group of DS. Furthermore, P.E.C.
In (A), the absorption near 1200 cm ^-1 (ν〓 _S SO ₂ ) shifts significantly compared to PEC (B) and the mixture, and the absorption is ^weak . Because it has no absorption, PEC
In (A), in addition to the ionic bond between the SO ₃ ^- group and the NH ₃ ⁺ group, the SO ₃ ^- group of DS seems to be bonded to the CH ₂ OH group or OH group of chitosan. Further, Table 1 shows the amount of thrombi and solubility in solvents in Examples 1 to 4 and Comparative Example 1 in the above-mentioned test method.

[Table] ○…Soluble, △…Soluble by heating,
×...Insoluble In Table 1, A is a ternary solvent (acetone:KBr:water=20:20:60), B is dimethylformamide, and C is dimethylsulfoxide. Moreover, from Table 1, it can be seen that the procoagulability of Examples 1 to 4 was significantly increased. moreover,
It can be seen that the PECs of Examples 1 to 4 are soluble even in solvents in which conventional PECs are insoluble.

[Brief explanation of the drawing]

FIG. 1 is an infrared absorption spectrum diagram of Example 1, Comparative Example 1, and a mixture of DS and chitosan.

Claims (1)

[Claims] 1. Reacting an anionic partially substituted dextran selected from dextran sulfate and carboxymethyl dextran with a cationic partially substituted polysaccharide selected from chitosan and diethylaminoethyl dextran or gelatin under acidic conditions with a pH of 3 or lower. A method for producing a polymer electrolyte complex, characterized by: